Uterine leiomyomata (fibroids) represent the most prevalent benign gynecologic disorder in the US. The cellular and molecular mechanisms regulating the development and growth of leiomyoma are not well understood. Our multidisciplinary team has designed 3 well-integrated projects focusing on Interactions between biologically critical hormonal pathways in uterine leiomyoma involving the transcription factors progesterone receptor (PR) and FOXO, the signaling pathway PI3K/AKT and the pro-fibrotic factor TGF-beta. Project I (Bulun) will be pursued to understand the mechanisms as to how antl-progestins such as RU486 reduce tumor size. We hypothesize that progesterone regulates a number of critical genes, that favors increased proliferation and decreased apoptosis of leiomyoma smooth muscle cells, whereas anti-progestins reverse this effect by enhancing apoptosis and decreasing proliferation. Project II (Kim/Chakravarti) will determine the role of the PI3K/AKT/F0X0 signaling pathway regulating leiomyoma cell growth and survival in response to progesterone. We hypothesize that progesterone Induces proliferation of leiomyoma cells through activation of the PI3K/AKT/F0X0 signaling pathway and that Inhibitors of the AKT pathway should override the proliferative effects of progesterone and promote apoptosis. Project III (Nowak) will define the mechanisms as to how antifibrotic drugs regulate leiomyoma growth. We hypothesize that the increased proliferation exhibited by leiomyoma smooth muscle cells Is due to a major shift in the extracellular matrix environment caused by increased synthesis of new, monomeric collagen type I by these cells. We will determine whether antifibrotic drugs may be an effective new treatment for leiomyomas. These projects are supported by an Administrative Core (Bulun) and Tissue Procurement and Cell Culture Core (Kurita). Overall, as part of our long range goal, all projects investigate local hormonal signaling regulating apoptosis and proliferation as biologic endpoints and test existing and upcoming pharmaceutical compounds that target these pathways in uterine leiomyomata. RELEVANCE (See instructions): Symptomatic uterine leiomyomata affect millions of US women and cause irregular uterine bleeding, anemia, recurrent pregnancy loss leading to more than 200,000 hysterectomies per year. Available treatments are limited due in large part to the fact that the mechanisms regulating the development and growth of these tumors are unclear. We propose integrated molecular, cellular and translational studies that should lead to a better understanding and future development of novel therapeutics for uterine leiomyomata.